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Šeškutė M, Žukaitė D, Laucaitytė G, Inčiūraitė R, Malinauskas M, Jankauskaitė L. Antiviral Effect of Melatonin on Caco-2 Cell Organoid Culture: Trick or Treat? Int J Mol Sci 2024; 25:11872. [PMID: 39595940 PMCID: PMC11594462 DOI: 10.3390/ijms252211872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/28/2024] [Accepted: 10/31/2024] [Indexed: 11/28/2024] Open
Abstract
Melatonin is a hormone naturally produced by the body that has recently been found to have antiviral properties. However, its antiviral mechanisms are not entirely understood. Using Caco-2 cells, we developed a gastrointestinal organoid model to investigate the impact of melatonin on cellular organoid culture response to Poly I:C-induced viral inflammation in the gastrointestinal tract. Melatonin was found to have different effect when applied as a pretreatment before the induction of viral inflammation or as a treatment after it. Melatonin pretreatment after Poly I:C stimulation did not protect organoids from size reduction but enhanced cell proliferation, especially when lower (1 and 10 µM) melatonin concentrations were used. On the other hand, treatment with melatonin after the induction of viral inflammation helped to maintain the size of the organoids while reducing cell proliferation. In pretreated cells, reduced IFNLR1 expression was found, while melatonin treatment increased IFNLR1 expression and reduced the production of viral cytokines, such as IFNλ1 and STAT1-3, but did not prevent from apoptosis. The findings of this study emphasize the importance of type III IFNs in antiviral defense in epithelial gastrointestinal cells and shed more light on the antiviral properties of melatonin as a potential therapeutic substance.
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Affiliation(s)
- Milda Šeškutė
- Department of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (M.Š.); (G.L.)
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Dominyka Žukaitė
- Faculty of Medicine, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Goda Laucaitytė
- Department of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (M.Š.); (G.L.)
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Rūta Inčiūraitė
- Institute for Digestive Research, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Mantas Malinauskas
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
| | - Lina Jankauskaitė
- Department of Pediatrics, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania; (M.Š.); (G.L.)
- Institute of Physiology and Pharmacology, Lithuanian University of Health Sciences, 44307 Kaunas, Lithuania;
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Li Y, Hung SW, Zheng X, Ding Y, Zhang T, Tan Z, Zhang R, Lin Y, Song Y, Wang Y, Wang CC. Melatonin Inhibits Endometriosis Growth via Specific Binding and Inhibition of EGFR Phosphorylation. J Pineal Res 2024; 76:e70022. [PMID: 39711424 DOI: 10.1111/jpi.70022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 12/24/2024]
Abstract
As a chronic gynecological disease, endometriosis is defined as the implantation of endometrial glands as well as stroma outside the uterine cavity. Proliferation is a major pathophysiology in endometriosis. Previous studies demonstrated a hormone named melatonin, which is mainly produced by the pineal gland, exerts a therapeutic impact on endometriosis. Despite that, the direct binding targets and underlying molecular mechanism have remained unknown. Our study revealed that melatonin treatment might be effective in inhibiting the growth of lesions in endometriotic mouse model as well as in human endometriotic cell lines. Additionally, the drug-disease protein-protein interaction (PPI) network was built, and epidermal growth factor receptor (EGFR) was identified as a new binding target of melatonin treatment in endometriosis. Computational simulation together with BioLayer interferometry was further applied to confirm the binding affinity. Our result also showed melatonin inhibited the phosphorylation level of EGFR not only in endometriotic cell lines but also in mouse models. Furthermore, melatonin inhibited the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt) pathway and arrested the cell cycle via inhibiting CyclinD1 (CCND1). In vitro and in vivo knockdown/restore assays further demonstrated the involvement of the binding target and signaling pathway that we found. Thus, melatonin can be applied as a novel therapy for the management of endometriosis.
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Affiliation(s)
- Yiran Li
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Sze-Wan Hung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Xu Zheng
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Yang Ding
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Tao Zhang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Zhouyurong Tan
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Ruizhe Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuezhen Lin
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Yi Song
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Yao Wang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi-Chiu Wang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China
- Reproduction and Development, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong, China
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Al-Ansari N, Samuel SM, Büsselberg D. Unveiling the Protective Role of Melatonin in Osteosarcoma: Current Knowledge and Limitations. Biomolecules 2024; 14:145. [PMID: 38397382 PMCID: PMC10886489 DOI: 10.3390/biom14020145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/18/2024] [Accepted: 01/21/2024] [Indexed: 02/25/2024] Open
Abstract
Melatonin, an endogenous neurohormone produced by the pineal gland, has received increased interest due to its potential anti-cancer properties. Apart from its well-known role in the sleep-wake cycle, extensive scientific evidence has shown its role in various physiological and pathological processes, such as inflammation. Additionally, melatonin has demonstrated promising potential as an anti-cancer agent as its function includes inhibition of tumorigenesis, induction of apoptosis, and regulation of anti-tumor immune response. Although a precise pathophysiological mechanism is yet to be established, several pathways related to the regulation of cell cycle progression, DNA repair mechanisms, and antioxidant activity have been implicated in the anti-neoplastic potential of melatonin. In the current manuscript, we focus on the potential anti-cancer properties of melatonin and its use in treating and managing pediatric osteosarcoma. This aggressive bone tumor primarily affects children and adolescents and is treated mainly by surgical and radio-oncological interventions, which has improved survival rates among affected individuals. Significant disadvantages to these interventions include disease recurrence, therapy-related toxicity, and severe/debilitating side effects that the patients have to endure, significantly affecting their quality of life. Melatonin has therapeutic effects when used for treating osteosarcoma, attributed to its ability to halt cancer cell proliferation and trigger apoptotic cell death, thereby enhancing chemotherapeutic efficacy. Furthermore, the antioxidative function of melatonin alleviates harmful side effects of chemotherapy-induced oxidative damage, aiding in decreasing therapeutic toxicities. The review concisely explains the many mechanisms by which melatonin targets osteosarcoma, as evidenced by significant results from several in vitro and animal models. Nevertheless, if further explored, human trials remain a challenge that could shed light and support its utility as an adjunctive therapeutic modality for treating osteosarcoma.
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Affiliation(s)
- Nojoud Al-Ansari
- Department of Medical Education, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar;
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha P.O. Box 24144, Qatar
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Bagherifard A, Hosseinzadeh A, Koosha F, Sheibani M, Karimi-Behnagh A, Reiter RJ, Mehrzadi S. Melatonin and bone-related diseases: an updated mechanistic overview of current evidence and future prospects. Osteoporos Int 2023; 34:1677-1701. [PMID: 37393580 DOI: 10.1007/s00198-023-06836-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 06/16/2023] [Indexed: 07/04/2023]
Abstract
PURPOSE Bone diseases account for an enormous cost burden on health systems. Bone disorders are considered as age-dependent diseases. The aging of world population has encouraged scientists to further explore the most effective preventive modalities and therapeutic strategies to overcome and reduce the high cost of bone disorders. Herein, we review the current evidence of melatonin's therapeutic effects on bone-related diseases. METHODS This review summarized evidences from in vitro, in vivo, and clinical studies regarding the effects of melatonin on bone-related diseases, with a focus on the molecular mechanisms. Electronically, Scopus and MEDLINE®/PubMed databases were searched for articles published on melatonin and bone-related diseases from inception to June 2023. RESULTS The findings demonstrated that melatonin has beneficial effect in bone- and cartilage-related disorders such as osteoporosis, bone fracture healing, osteoarthritis, and rheumatoid arthritis, in addition to the control of sleep and circadian rhythms. CONCLUSION A number of animal and clinical studies have indicated that various biological effects of melatonin may suggest this molecule as an effective therapeutic agent for controlling, diminishing, or suppressing bone-related disorders. Therefore, further clinical studies are required to clarify whether melatonin can be effective in patients with bone-related diseases.
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Affiliation(s)
- Abolfazl Bagherifard
- Bone and Joint Reconstruction Research Center, Department of Orthopedics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Koosha
- Department of Radiology Technology, Faculty of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Sheibani
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Russel J Reiter
- Department of Cellular and Structural Biology, Long School of Medicine, UT Health San Antonio, San Antonio, TX, USA
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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Shukla M, Vincent B. Melatonin as a Harmonizing Factor of Circadian Rhythms, Neuronal Cell Cycle and Neurogenesis: Additional Arguments for Its Therapeutic Use in Alzheimer's Disease. Curr Neuropharmacol 2023; 21:1273-1298. [PMID: 36918783 PMCID: PMC10286584 DOI: 10.2174/1570159x21666230314142505] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/07/2022] [Accepted: 12/31/2022] [Indexed: 03/16/2023] Open
Abstract
The synthesis and release of melatonin in the brain harmonize various physiological functions. The apparent decline in melatonin levels with advanced aging is an aperture to the neurodegenerative processes. It has been indicated that down regulation of melatonin leads to alterations of circadian rhythm components, which further causes a desynchronization of several genes and results in an increased susceptibility to develop neurodegenerative diseases. Additionally, as circadian rhythms and memory are intertwined, such rhythmic disturbances influence memory formation and recall. Besides, cell cycle events exhibit a remarkable oscillatory system, which is downstream of the circadian phenomena. The linkage between the molecular machinery of the cell cycle and complex fundamental regulatory proteins emphasizes the conjectural regulatory role of cell cycle components in neurodegenerative disorders such as Alzheimer's disease. Among the mechanisms intervening long before the signs of the disease appear, the disturbances of the circadian cycle, as well as the alteration of the machinery of the cell cycle and impaired neurogenesis, must hold our interest. Therefore, in the present review, we propose to discuss the underlying mechanisms of action of melatonin in regulating the circadian rhythm, cell cycle components and adult neurogenesis in the context of AD pathogenesis with the view that it might further assist to identify new therapeutic targets.
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Affiliation(s)
- Mayuri Shukla
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
- Present Address: Chulabhorn Graduate Institute, Chulabhorn Royal Academy, 10210, Bangkok, Thailand
| | - Bruno Vincent
- Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom 73170, Thailand
- Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France
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Gong YQ, Hou FT, Xiang CL, Li CL, Hu GH, Chen CW. The mechanisms and roles of melatonin in gastrointestinal cancer. Front Oncol 2022; 12:1066698. [PMID: 36591447 PMCID: PMC9798083 DOI: 10.3389/fonc.2022.1066698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022] Open
Abstract
Gastrointestinal (GI) cancer is a global health problem with wide lesions and numerous cases. The increased morbidity and mortality of GI cancer is a socio-economic challenge for decades to come. Melatonin, a nature indolamine, exerts a crucial role in molecular interactions involved in multiple functional and physiological processes. Increasing evidence indicates that melatonin can modulate GI tract, decrease the occurrence of GI cancer, and enhance the sensitivity to chemoradiotherapy. However, little is known about the exact role of melatonin in anti-carcinogenesis. In this review, we discuss the action of the beneficial effects of melatonin in GI carcinogenesis. Furthermore, we compile the understanding of the role of melatonin in GI cancer, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer (PC). In addition, the potential therapeutic application and clinical evaluation of melatonin in GI cancer are also discussed.
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Affiliation(s)
- Yong-Qiang Gong
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Fu-Tao Hou
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Cai-Ling Xiang
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Cheng-Long Li
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Guo-Huang Hu
- Department of General Surgery, Institute of Digestive Surgery of Changsha, Affiliated Changsha Hospital of Hunan Normal University, Changsha, Hunan, China,*Correspondence: Guo-Huang Hu, ; Chao-Wu Chen,
| | - Chao-Wu Chen
- Department of Gastrointestinal Surgery, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China,*Correspondence: Guo-Huang Hu, ; Chao-Wu Chen,
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8
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Xu N, Wang X, Wang L, Song Y, Zheng X, Hu H. Comprehensive analysis of potential cellular communication networks in advanced osteosarcoma using single-cell RNA sequencing data. Front Genet 2022; 13:1013737. [PMID: 36303551 PMCID: PMC9592772 DOI: 10.3389/fgene.2022.1013737] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022] Open
Abstract
Osteosarcoma (OS) is a common bone cancer in children and adolescents, and metastasis and recurrence are the major causes of poor treatment outcomes. A better understanding of the tumor microenvironment is required to develop an effective treatment for OS. In this paper, a single-cell RNA sequencing dataset was taken to a systematic genetic analysis, and potential signaling pathways linked with osteosarcoma development were explored. Our findings revealed 25 clusters across 11 osteosarcoma tissues, with 11 cell types including “Chondroblastic cells”, “Osteoblastic cells”, “Myeloid cells”, “Pericytes”, “Fibroblasts”, “Proliferating osteoblastic cells”, “Osteoclasts”, “TILs”, “Endothelial cells”, “Mesenchymal stem cells”, and “Myoblasts”. The results of Cell communication analysis showed 17 potential cellular communication networks including “COLLAGEN signaling pathway network”, “CD99 signaling pathway network”, “PTN signaling pathway network”, “MIF signaling pathway network”, “SPP1 signaling pathway network”, “FN1 signaling pathway network”, “LAMININ signaling pathway network”, “FGF signaling pathway network”, “VEGF signaling pathway network”, “GALECTIN signaling pathway network”, “PERIOSTIN signaling pathway network”, “VISFATIN signaling pathway network”, “ITGB2 signaling pathway network”, “NOTCH signaling pathway network”, “IGF signaling pathway network”, “VWF signaling pathway network”, “PDGF signaling pathway network”. This research may provide novel insights into the pathophysiology of OS’s molecular processes.
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Affiliation(s)
- Ning Xu
- Departments of Orthopedics, Shanghai Eighth People’s Hospital, Shanghai, China
| | - Xiaojing Wang
- Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lili Wang
- Departments of Orthopedics, Shanghai Eighth People’s Hospital, Shanghai, China
| | - Yuan Song
- Departments of Orthopedics, Shanghai Eighth People’s Hospital, Shanghai, China
- *Correspondence: Yuan Song, ; Xianyou Zheng, ; Hai Hu,
| | - Xianyou Zheng
- Departments of Orthopedics, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yuan Song, ; Xianyou Zheng, ; Hai Hu,
| | - Hai Hu
- Departments of Orthopedics, Shanghai Eighth People’s Hospital, Shanghai, China
- Departments of Orthopedics, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Yuan Song, ; Xianyou Zheng, ; Hai Hu,
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Abstract
The pineal gland is a interface between light-dark cycle and shows neuro-endocrine functions. Melatonin is the primary hormone of pineal gland, secreted at night. The night-time melatonin peak regulates the physiological functions at dark. Melatonin has several unique features as it synchronises internal rhythm with daily and seasonal variations, regulates circadian rhythm and sleep-wake cycle. Physiologically melatonin involves in detoxification of free radicals, immune functions, neuro-protection, oncostatic effects, cardiovascular functions, reproduction, and foetal development. The precise functions of melatonin are exhibited by specific receptors. In relation to pathophysiology, impaired melatonin secretion promotes sleep disorder, cancer progression, type-2 diabetes, and neurodegenerative diseases. Several reports have highlighted the therapeutic benefits of melatonin specially related to cancer protection, sleep disorder, psychiatric disorders, and jet lag problems. This review will touch the most of the area of melatonin-oriented health impacts and its therapeutic aspects.
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Li Y, Hung SW, Zhang R, Man GCW, Zhang T, Chung JPW, Fang L, Wang CC. Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight. Nutrients 2022; 14:nu14194087. [PMID: 36235740 PMCID: PMC9572886 DOI: 10.3390/nu14194087] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.
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Affiliation(s)
- Yiran Li
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Sze-Wan Hung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ruizhe Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Gene Chi-Wai Man
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Tao Zhang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jacqueline Pui-Wah Chung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
| | - Chi-Chiu Wang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
- Laboratory of Reproduction and Development, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
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11
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Moradian F, Pourhanifeh MH, Mehrzadi S, Karimi‐Behnagh A, Hosseinzadeh A. Therapeutic potentials of melatonin in the treatment of lymphoma: A review of current evidence. Fundam Clin Pharmacol 2022; 36:777-789. [DOI: 10.1111/fcp.12780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/03/2022] [Accepted: 04/04/2022] [Indexed: 11/29/2022]
Affiliation(s)
- Farid Moradian
- Departement of General Surgery Alborz University of Medical Science Alborz Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences Kashan University of Medical Sciences Kashan Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center Iran University of Medical Sciences Tehran Iran
| | | | - Azam Hosseinzadeh
- Razi Drug Research Center Iran University of Medical Sciences Tehran Iran
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12
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Targhazeh N, Reiter RJ, Rahimi M, Qujeq D, Yousefi T, Shahavi MH, Mir SM. Oncostatic activities of melatonin: Roles in cell cycle, apoptosis, and autophagy [Biochimie 200 (2022) 44-59]. Biochimie 2022; 200:44-59. [PMID: 35618158 DOI: 10.1016/j.biochi.2022.05.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 12/11/2022]
Affiliation(s)
- Niloufar Targhazeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX, USA
| | - Mahdi Rahimi
- Lodz University of Technology, Institute of Polymer and Dye Technology, Stefanowskiego 16, 90-537, Lodz, Poland; International Center for Research on Innovative Biobased Materials (ICRI-BioM)-International Research Agenda, Lodz University of Technology, Lodz, Poland
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Tooba Yousefi
- Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Iran
| | - Mohammad Hassan Shahavi
- Department of Nanotechnology, Faculty of Engineering Modern Technologies, Amol University of Special Modern Technologies, Amol, Iran
| | - Seyed Mostafa Mir
- Metabolic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Golestan University of Medical Sciences, Babol, Iran.
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Abstract
Melatonin, the major secretory product of the pineal gland, not only regulates circadian rhythms, mood, and sleep but also has actions in neoplastic processes which are being intensively investigated. Melatonin is a promising molecule which considered a differentiating agent in some cancer cells at both physiological and pharmacological concentrations. It can also reduce invasive and metastatic status through receptors MT1 and MT2 cytosolic binding sites, including calmodulin and quinone reductase II enzyme, and nuclear receptors related to orphan members of the superfamily RZR/ROR. Melatonin exerts oncostatic functions in numerous human malignancies. An increasing number of studies report that melatonin reduces the invasiveness of several human cancers such as prostate cancer, breast cancer, liver cancer, oral cancer, lung cancer, ovarian cancer, etc. Moreover, melatonin's oncostatic activities are exerted through different biological processes including antiproliferative actions, stimulation of anti-cancer immunity, modulation of the cell cycle, apoptosis, autophagy, the modulation of oncogene expression, and via antiangiogenic effects. This review focuses on the oncostatic activities of melatonin that targeted cell cycle control, with special attention to its modulatory effects on the key regulators of the cell cycle, apoptosis, and telomerase activity.
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Fu B, YilinYao, Heng D, Li N, Ma X, Wang Q, Yang Y, Zhang C. The Effect of Melatonin on OCT4 Expression and Granulosa Cell Growth in Female Mice. Reprod Sci 2021; 29:2810-2819. [PMID: 34735714 DOI: 10.1007/s43032-021-00783-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/24/2021] [Indexed: 10/19/2022]
Abstract
Melatonin is mainly secreted by the pineal gland as a neurotransmitter. Moreover, melatonin is also produced by the ovary and plays important roles in female reproduction. However, it is unclear whether melatonin has any effect on the transition from the preantral follicle to the early antral follicle. Octamer-binding transcription factor 4 (OCT4) is important to granulosa cells development, which is regulated by gonadotropin. And these regulations are mediated by the GSK3β/β-catenin pathway via the activated PI3K/Akt signaling. The aim of the present study was to determine the effects and the possible mechanisms of melatonin on ovarian cells development. The results showed that melatonin inhibited granulosa cells development, which was accompanied by the downregulation of OCT4 expression. Meanwhile, melatonin also decreased the expression of p-GSK3β (glycogen synthase kinase 3 beta), p-Akt, β-catenin, and its translocation to the nucleus in granulosa cells. Moreover, melatonin attenuated the effects of FSH in vitro and eCG in vivo on these regulations. In conclusion, this study shows that melatonin inhibits ovarian cell development by downregulating the OCT4 expression level, which is possibly mediated by inhibiting the PI3K/Akt and GSK3β/β-catenin pathway. Melatonin attenuates the effects of gonadotropin on ovarian granulosa cells as a negative regulator.
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Affiliation(s)
- Baoqiang Fu
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - YilinYao
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - Dai Heng
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - Ningxin Li
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - Xiaoshu Ma
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - Qiaozhi Wang
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China
| | - Yanzhou Yang
- Key Laboratory of Fertility Preservation and Maintenance, Ministry of Education, Key Laboratory of Reproduction and Genetics in Ningxia, Department of Histology and Embryology, Ningxia Medical University, Ningxia, 750004, People's Republic of China.
| | - Cheng Zhang
- College of Life Science, Capital Normal University, Beijing, 100048, People's Republic of China.
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15
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Ragothaman M, Kannan Villalan A, Dhanasekaran A, Palanisamy T. Bio-hybrid hydrogel comprising collagen-capped silver nanoparticles and melatonin for accelerated tissue regeneration in skin defects. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 128:112328. [PMID: 34474879 DOI: 10.1016/j.msec.2021.112328] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/29/2021] [Accepted: 07/18/2021] [Indexed: 01/22/2023]
Abstract
Hydrogel-based drug delivery systems have emerged as a promising platform for chronic tissue defects owing to their inherent ability to inhibit pathogenic infection and accelerate rapid tissue regeneration. Here, we fabricated a stable bio-hybrid hydrogel system comprising collagen, aminated xanthan gum, bio-capped silver nanoparticles and melatonin with antimicrobial, antioxidant and anti-inflammatory properties. Highly colloidal bio-capped silver nanoparticles were synthesized using collagen as a reducing cum stabilizing agent for the first time while aminated xanthan gum was synthesized using ethylenediamine treatment on xanthan gum. The synthesized bio-hybrid hydrogel exhibits better gelation, surface morphology, rheology and degelation properties. In vitro assessment of bio-hybrid hydrogel demonstrates excellent bactericidal efficiency against both common wound and multidrug-resistant pathogens and biocompatibility properties. In vivo animal studies demonstrate rapid tissue regeneration, collagen deposition and angiogenesis at the wound site predominantly due to the synergistic effect of silver nanoparticles and melatonin in the hydrogel. This study paves the way for developing biologically functional bio-nano hydrogel systems for promoting effective care for various ailments, including infected chronic wounds.
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Affiliation(s)
- Murali Ragothaman
- Centre for Biotechnology, Anna University, Chennai 600025, India; Advanced Materials Laboratory, Central Leather Research Institute (Council of Scientific and Industrial Research), Adyar, Chennai 600020, India
| | - Arivizhivendhan Kannan Villalan
- Advanced Materials Laboratory, Central Leather Research Institute (Council of Scientific and Industrial Research), Adyar, Chennai 600020, India
| | | | - Thanikaivelan Palanisamy
- Advanced Materials Laboratory, Central Leather Research Institute (Council of Scientific and Industrial Research), Adyar, Chennai 600020, India.
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Zhang W, Zhao W, Li Q, Zhao D, Qu J, Yuan Z, Cheng Z, Zhu X, Zhuang X, Zhang Z. 3D-printing magnesium-polycaprolactone loaded with melatonin inhibits the development of osteosarcoma by regulating cell-in-cell structures. J Nanobiotechnology 2021; 19:263. [PMID: 34481503 PMCID: PMC8418751 DOI: 10.1186/s12951-021-01012-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/24/2021] [Indexed: 12/30/2022] Open
Abstract
Melatonin has been proposed as a potent anticarcinogen presents a short half-life for osteosarcoma (OS). Cell-in-cell (CIC) structures play a role in the development of malignant tumors by changing the tumor cell energy metabolism. This study developed a melatonin-loaded 3D printed magnesium-polycaprolactone (Mg-PCL) scaffold and investigated its effect and molecular mechanism on CIC in OS. Mg-PCL scaffold was prepared by 3D-printing and its characteristic was determined. The effect and molecular mechanism of Mg-PCL scaffold as well as melatonin-loaded Mg-PCL on OS growth and progression were investigated in vivo and in vitro. We found that melatonin receptor 1 (MT1) and CIC expressions were increased in OS tissues and cells. Melatonin treatment inhibit the key CIC pathway, Rho/ROCK, through the cAMP/PKA signaling pathway, interfering with the mitochondrial physiology of OS cells, and thus playing an anti-invasion and anti-metastasis role in OS. The Mg-PCL-MT could significantly inhibit distant organ metastasis of OS in the in vivo model. Our results showed that melatonin-loaded Mg-PCL scaffolds inhibited the proliferation, invasion and metastasis of OS cells through the CIC pathway. The Mg-PCL-MT could be a potential therapeutics for OS.
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Affiliation(s)
- Weilin Zhang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Wei Zhao
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Qin Li
- Translational Medicine Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Duoyi Zhao
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Junxing Qu
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Ziyang Yuan
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Zhihong Cheng
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China
| | - Xiaojuan Zhu
- Key Laboratory of Molecular Epigenetics, Ministry of Education and Institute of Cytology and Genetics, Northeast Normal University, Changchun, Jilin, China
| | - Xiuli Zhuang
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry Chinese Academy of Sciences, Changchun, Jilin, China
| | - Zhiyu Zhang
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China.
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Gao XY, Deng BH, Li XR, Wang Y, Zhang JX, Hao XY, Zhao JX. Melatonin Regulates Differentiation of Sheep Brown Adipocyte Precursor Cells Via AMP-Activated Protein Kinase. Front Vet Sci 2021; 8:661773. [PMID: 34235199 PMCID: PMC8255384 DOI: 10.3389/fvets.2021.661773] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/10/2021] [Indexed: 01/10/2023] Open
Abstract
In sheep industry, hypothermia caused by insufficient brown adipose tissue (BAT) deposits is one of the major causes of lamb deaths. Enhancing the formation and function of BAT in neonatal lamb increases thermogenesis and hence reduces economic losses. The aim of the present study was to explore the effect and mechanism of melatonin on sheep brown adipocyte formation and function. Sheep brown adipocyte precursor cells (SBACs) isolated from perirenal BAT were treated with melatonin (1 and 10 nM). The SBACs subjected to melatonin exhibited a decreased proliferation ability, accompanied by down-regulated proliferating cell nuclear antigen, cyclin D1, and CDK4 protein contents in a melatonin dose-dependent manner. Melatonin promoted brown adipocyte formation and induced the expression of brown adipogenic markers, including uncoupling protein 1 and PR domain-containing 16 during differentiation of SBAC. Moreover, the AMP-activated protein kinase α1 (AMPKα1) activity was positively correlated with brown adipocyte formation potential. Importantly, melatonin effectively activated AMPKα1. Furthermore, promotional effects of melatonin were abolished by AMPKα1 knockout, suggesting the involvement of AMPKα1 in this process. Collectively, these results suggested that melatonin enhanced brown adipocyte formation in SBACs in vitro through activation of AMPKα1.
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Affiliation(s)
- Xu-Yang Gao
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Bu-Hao Deng
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Xin-Rui Li
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Yu Wang
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Jian-Xin Zhang
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Xiao-Yan Hao
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
| | - Jun-Xing Zhao
- College of Animal Science, Shanxi Agricultural University, Shanxi, China
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Yang L, Zhao Z, Cui M, Zhang L, Li Q. Melatonin Restores the Developmental Competence of Heat Stressed Porcine Oocytes, and Alters the Expression of Genes Related to Oocyte Maturation. Animals (Basel) 2021; 11:ani11041086. [PMID: 33920315 PMCID: PMC8069948 DOI: 10.3390/ani11041086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/06/2021] [Accepted: 04/08/2021] [Indexed: 01/31/2023] Open
Abstract
Simple Summary Melatonin improves the quality and in vitro maturation (IVM) of oocytes under heat stress. Melatonin treatment counteracts the adverse effects induced by heat stress (HS), such as the poor survival rate and maturation rate, distribution of α-tubulin and F-actin, expression of NRF2 and GDF9 mRNA. However, HS and melatonin have similar effects on increasing expression of HSP70 and NRF2 mRNA. Furthermore, HS inhibits expression of GDF9 mRNA. Abstract Melatonin enhances the quality and in vitro maturation (IVM) of oocytes under heat stress (HS), but the mechanism of melatonin in reducing HS injury on oocytes is not fully understood. In this study, porcine cumulus-oocyte complexes (COCs) were randomly divided into three groups. The COCs of the control group were cultured at 38.5 °C for 42 h, and the COCs of the HS group were cultured at 41.5 °C for 4 h, and then transferred into 38.5 °C for 38 h. The COCs of the HS + melatonin group were cultured with 10−9 M melatonin under the same conditions as the HS group. The survival rate, maturation rate, distribution of α-tubulin and F-actin of the oocytes were assessed. In addition, the expression profiles for genes related to the oocyte maturation, including heat shock protein 70 (HSP70), nuclear factor erythroid 2-related factor 2 (NRF2), cyclin-dependent kinase 1 (CDK1), growth differentiation factor 9 (GDF9) were analyzed by real-time quantitative PCR. The results showed that HS decreased the survival rate and maturation rate, distribution of α-tubulin and F-actin, but melatonin treatment could partly counteract these adverse effects. In addition, HS increased expression of HSP70 and NRF2 mRNA, and melatonin treatment had a similar effect on HSP70 expression, but had a contrary effect on NRF2 expression. Furthermore, HS inhibited expression of CDK1 and GDF9 mRNA, but melatonin treatment could weaken the effect on GDF9 expression induced by HS. In summary, melatonin treatment could attenuate the unfavorable effects induced by HS to enhance developmental competence of porcine oocytes during IVM.
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Affiliation(s)
- Ling Yang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China; (L.Y.); (Z.Z.); (L.Z.)
| | - Zimo Zhao
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China; (L.Y.); (Z.Z.); (L.Z.)
- Animal Husbandry and Veterinary Research Institute of Tianjin, Tianjin 300412, China;
| | - Maosheng Cui
- Animal Husbandry and Veterinary Research Institute of Tianjin, Tianjin 300412, China;
- Correspondence:
| | - Leying Zhang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China; (L.Y.); (Z.Z.); (L.Z.)
| | - Qianjun Li
- Animal Husbandry and Veterinary Research Institute of Tianjin, Tianjin 300412, China;
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Bilska B, Schedel F, Piotrowska A, Stefan J, Zmijewski M, Pyza E, Reiter RJ, Steinbrink K, Slominski AT, Tulic MK, Kleszczyński K. Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells. J Pineal Res 2021; 70:e12728. [PMID: 33650175 DOI: 10.1111/jpi.12728] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/19/2021] [Accepted: 02/23/2021] [Indexed: 12/16/2022]
Abstract
Melanoma is a leading cause of cancer deaths worldwide. Although immunotherapy has revolutionized the treatment for some patients, resistance towards therapy and unwanted side effects remain a problem for numerous individuals. Broad anti-cancer activities of melatonin are recognized; however, additional investigations still need to be elucidated. Herein, using various human melanoma cell models, we explore in vitro the new insights into the regulation of melanoma by melatonin and its metabolites which possess, on the other side, high safety profiles and biological meaningful. In this study, using melanotic (MNT-1) and amelanotic (A375, G361, Sk-Mel-28) melanoma cell lines, the comparative oncostatic responses, the impact on melanin content (for melanotic MNT-1 melanoma cells) as well as the mitochondrial function controlled by melatonin, its precursor (serotonin), a kynuric (N1 -acetyl-N2 -formyl-5-methoxykynuramine, AFMK) and indolic pathway (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) metabolites were assessed. Namely, significant disturbances were observed in bioenergetics as follows: (i) uncoupling of oxidative phosphorylation (OXPHOS), (ii) attenuation of glycolysis, (iii) dissipation of mitochondrial transmembrane potential (mtΔΨ) accompanied by (iv) massive generation of reactive oxygen species (ROS), and (v) decrease of glucose uptake. Collectively, these results together with previously published reports provide a new biological potential and make an imperative to consider using melatonin or its metabolites for complementary future treatments of melanoma-affected patients; however, these associations should be additionally investigated in clinical setting.
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Affiliation(s)
- Bernadetta Bilska
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Fiona Schedel
- Department of Dermatology, University of Münster, Münster, Germany
| | - Anna Piotrowska
- Department of Histology, Medical University of Gdańsk, Gdańsk, Poland
| | - Joanna Stefan
- Department of Oncology, Nicolaus Copernicus University Medical College, Bydgoszcz, Poland
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Michal Zmijewski
- Department of Histology, Medical University of Gdańsk, Gdańsk, Poland
| | - Elżbieta Pyza
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Russel J Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX, USA
| | | | - Andrzej T Slominski
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, USA
| | - Meri K Tulic
- Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France
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Bonmati-Carrion MA, Tomas-Loba A. Melatonin and Cancer: A Polyhedral Network Where the Source Matters. Antioxidants (Basel) 2021; 10:antiox10020210. [PMID: 33535472 PMCID: PMC7912767 DOI: 10.3390/antiox10020210] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Melatonin is one of the most phylogenetically conserved signals in biology. Although its original function was probably related to its antioxidant capacity, this indoleamine has been “adopted” by multicellular organisms as the “darkness signal” when secreted in a circadian manner and is acutely suppressed by light at night by the pineal gland. However, melatonin is also produced by other tissues, which constitute its extrapineal sources. Apart from its undisputed chronobiotic function, melatonin exerts antioxidant, immunomodulatory, pro-apoptotic, antiproliferative, and anti-angiogenic effects, with all these properties making it a powerful antitumor agent. Indeed, this activity has been demonstrated to be mediated by interfering with various cancer hallmarks, and different epidemiological studies have also linked light at night (melatonin suppression) with a higher incidence of different types of cancer. In 2007, the World Health Organization classified night shift work as a probable carcinogen due to circadian disruption, where melatonin plays a central role. Our aim is to review, from a global perspective, the role of melatonin both from pineal and extrapineal origin, as well as their possible interplay, as an intrinsic factor in the incidence, development, and progression of cancer. Particular emphasis will be placed not only on those mechanisms related to melatonin’s antioxidant nature but also on the recently described novel roles of melatonin in microbiota and epigenetic regulation.
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Affiliation(s)
- Maria-Angeles Bonmati-Carrion
- Chronobiology Laboratory, Department of Physiology, IMIB-Arrixaca, University of Murcia, 30100 Murcia, Spain
- Ciber Fragilidad y Envejecimiento Saludable, 28090 Madrid, Spain
- Correspondence: (M.-A.B.-C.); (A.T.-L.)
| | - Antonia Tomas-Loba
- Circadian Rhythm and Cancer Laboratory, Department of Physiology, IMIB-Arrixaca, University of Murcia, 30120 Murcia, Spain
- Correspondence: (M.-A.B.-C.); (A.T.-L.)
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21
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New insights into antimetastatic signaling pathways of melatonin in skeletomuscular sarcoma of childhood and adolescence. Cancer Metastasis Rev 2020; 39:303-320. [PMID: 32086631 DOI: 10.1007/s10555-020-09845-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Melatonin is an indole produced by the pineal gland at night under normal light or dark conditions, and its levels, which are higher in children than in adults, begin to decrease prior to the onset of puberty and continue to decline thereafter. Apart from circadian regulatory actions, melatonin has significant apoptotic, angiogenic, oncostatic, and antiproliferative effects on various cancer cells. Particularly, the ability of melatonin to inhibit skeletomuscular sarcoma, which most commonly affects children, teenagers, and young adults, is substantial. In the past few decades, the vast majority of references have focused on the concept of epithelial-mesenchymal transition involvement in invasion and migration to allow carcinoma cells to dissociate from each other and to degrade the extracellular matrix. Recently, researchers have applied this idea to sarcoma cells of mesenchymal origin, e.g., osteosarcoma and Ewing sarcoma, with their ability to initiate the invasion-metastasis cascade. Similarly, interest of the effects of melatonin has shifted from carcinomas to sarcomas. Herein, in this state-of-the-art review, we compiled the knowledge related to the molecular mechanism of antimetastatic actions of melatonin on skeletomuscular sarcoma as in childhood and during adolescence. Utilization of melatonin as an adjuvant with chemotherapeutic drugs for synergy and fortification of the antimetastatic effects for the reinforcement of therapeutic actions are considered.
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22
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Hao EY, Wang DH, Chang LY, Huang CX, Chen H, Yue QX, Zhou RY, Huang RL. Melatonin regulates chicken granulosa cell proliferation and apoptosis by activating the mTOR signaling pathway via its receptors. Poult Sci 2020; 99:6147-6162. [PMID: 33142533 PMCID: PMC7647829 DOI: 10.1016/j.psj.2020.08.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 07/24/2020] [Accepted: 08/06/2020] [Indexed: 12/17/2022] Open
Abstract
Melatonin is a key regulator of follicle granular cell maturation and ovulation. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell growth regulation. Therefore, our aim was to investigate whether the mTOR signaling pathway is involved in the regulation of melatonin-mediated proliferation and apoptotic mechanisms in granulosa cells. Chicken follicle granular cells were cultured with melatonin (0, 2, 20, or 200 μmol/L) for 48 h. The results showed that melatonin treatment enhanced proliferation and suppressed apoptosis in granular cells at 20 μmol/L and 200 μmol/L (P < 0.05) by upregulation of cyclin D1 (P < 0.01) and Bcl-2 (P < 0.01) and downregulation of P21, caspase-3, Beclin1, and LC3-II (P < 0.01). The effects resulted in the activation of the mTOR signaling pathway by increasing the expression of avTOR, PKC, 4E-BP1, S6K (P < 0.05), p-mTOR, and p-S6K. We added an mTOR activator and inhibitor to the cells and identified the optimal dose (10 μmol/L MHY1485 and 100 nmol/L rapamycin) for subsequent experiments. The combination of 20 μmol/L melatonin and 10 μmol/L MHY1485 significantly enhanced granulosa cell proliferation (P < 0.05), while 100 nmol/L rapamycin significantly inhibited proliferation and enhanced apoptosis (P < 0.05), but this action was reversed in the 20-μmol/L melatonin and 100-nmol/L rapamycin cotreatment groups (P < 0.05). This was confirmed by mRNA and protein expression that was associated with proliferation, apoptosis, and autophagy (P < 0.05). The combination of 20 μmol/L melatonin and 10 μmol/L MHY1485 also activated the mTOR pathway upstream genes PI3K, AKT1, and AKT2 and downstream genes PKC, 4E-BP1, and S6K (P < 0.05), as well as protein expression of p-mTOR and p-S6K. Rapamycin significantly inhibited the mTOR pathway-related genes mRNA levels (P < 0.05). In addition, activation of the mTOR pathway increased melatonin receptor mRNA levels (P < 0.05). In conclusion, these findings demonstrate that melatonin regulates chicken granulosa cell proliferation and apoptosis by activating the mTOR signaling pathway via its receptor.
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Affiliation(s)
- Er-Ying Hao
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
| | - De-He Wang
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
| | - Li-Yun Chang
- College of Veterinary Medicine, Hebei Agricultural University, Baoding Hebei 071001, China
| | - Chen-Xuan Huang
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
| | - Hui Chen
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China.
| | - Qiao-Xian Yue
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
| | - Rong-Yan Zhou
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
| | - Ren-Lu Huang
- College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China
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Liu J, Wu S, Xie X, Wang Z, Lei Q. Identification of potential crucial genes and key pathways in osteosarcoma. Hereditas 2020; 157:29. [PMID: 32665038 PMCID: PMC7362476 DOI: 10.1186/s41065-020-00142-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 07/03/2020] [Indexed: 12/12/2022] Open
Abstract
Background The aim of this study is to identify the potential pathogenic and metastasis-related differentially expressed genes (DEGs) in osteosarcoma through bioinformatic analysis of Gene Expression Omnibus (GEO) database. Results Gene expression profiles of GSE14359, GSE16088, and GSE33383, in total 112 osteosarcoma tissue samples and 7 osteoblasts, were analyzed. Seventy-four normal-primary DEGs (NPDEGs) and 764 primary-metastatic DEGs (PMDEGs) were screened. VAMP8, A2M, HLA-DRA, SPARCL1, HLA-DQA1, APOC1 and AQP1 were identified continuously upregulating during the oncogenesis and metastasis of osteosarcoma. The enriched functions and pathways of NPDEGs include procession and presentation of antigens, activation of MHC class II receptors and phagocytosis. The enriched functions and pathways of PMDEGs include mitotic nuclear division, cell adhesion molecules (CAMs) and focal adhesion. With protein-protein interaction (PPI) network analyzed by Molecular Complex Detection (MCODE) plug-in of Cytoscape software, one hub NPDEG (HLA-DRA) and 7 hub PMDEGs (CDK1, CDK20, CCNB1, MTIF2, MRPS7, VEGFA and EGF) were eventually selected, and the most significant pathways in NPDEGs module and PMDEGs module were enriched in the procession and presentation of exogenous peptide antigen via MHC class II and the nuclear division, respectively. Conclusions By integrated bioinformatic analysis, numerous DEGs related to osteosarcoma were screened, and the hub DEGs identified in this study are possibly part of the potential biomarkers for osteosarcoma. However, further experimental studies are still necessary to elucidate the biological function and mechanism of these genes.
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Affiliation(s)
- Junwei Liu
- Department of Orthopedic surgery, Daping Hospital, Army medical university, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, PR China
| | - Siyu Wu
- Department of Orthopedic surgery, Daping Hospital, Army medical university, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, PR China
| | - Xiaoyu Xie
- Department of Orthopedic surgery, Daping Hospital, Army medical university, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, PR China
| | - Ziming Wang
- Department of Orthopedic surgery, Daping Hospital, Army medical university, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, PR China.
| | - Qianqian Lei
- Department of Radiation Oncology, Chongqing University Cancer Hospital, No. 181, Hanyu road, Shapingba District, Chongqing, 400030, PR China.
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Samanta S. Melatonin: an endogenous miraculous indolamine, fights against cancer progression. J Cancer Res Clin Oncol 2020; 146:1893-1922. [PMID: 32583237 DOI: 10.1007/s00432-020-03292-w] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Melatonin is an amphipathic indolamine molecule ubiquitously present in all organisms ranging from cyanobacteria to humans. The pineal gland is the site of melatonin synthesis and secretion under the influence of the retinohypothalamic tract. Some extrapineal tissues (skin, lens, gastrointestinal tract, testis, ovary, lymphocytes, and astrocytes) also enable to produce melatonin. Physiologically, melatonin regulates various functions like circadian rhythm, sleep-wake cycle, gonadal activity, redox homeostasis, neuroprotection, immune-modulation, and anticancer effects in the body. Inappropriate melatonin secretion advances the aging process, tumorigenesis, visceral adiposity, etc. METHODS: For the preparation of this review, I had reviewed the literature on the multidimensional activities of melatonin from the NCBI website database PubMed, Springer Nature, Science Direct (Elsevier), Wiley Online ResearchGate, and Google Scholar databases to search relevant articles. Specifically, I focused on the roles and mechanisms of action of melatonin in cancer prevention. RESULTS The actions of melatonin are primarily mediated by G-protein coupled MT1 and MT2 receptors; however, several intracellular protein and nuclear receptors can modulate the activity. Normal levels of the melatonin protect the cells from adverse effects including carcinogenesis. Therapeutically, melatonin has chronomedicinal value; it also shows a remarkable anticancer property. The oncostatic action of melatonin is multidimensional, associated with the advancement of apoptosis, the arrest of the cell cycle, inhibition of metastasis, and antioxidant activity. CONCLUSION The present review has emphasized the mechanism of the anti-neoplastic activity of melatonin that increases the possibilities of the new approaches in cancer therapy.
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Affiliation(s)
- Saptadip Samanta
- Department Physiology, Midnapore College, Paschim Medinipur, Midnapore, West Bengal, 721101, India.
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25
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Estaras M, Peña FJ, Tapia JA, Fernandez-Bermejo M, Mateos JM, Vara D, Roncero V, Blanco G, Lopez D, Salido GM, Gonzalez A. Melatonin modulates proliferation of pancreatic stellate cells through caspase-3 activation and changes in cyclin A and D expression. J Physiol Biochem 2020; 76:345-355. [PMID: 32361979 DOI: 10.1007/s13105-020-00740-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Abstract
In this study, the effects of melatonin (1 μM-1 mM) on pancreatic stellate cells (PSC) have been examined. Cell viability and proliferation, caspase-3 activation, and the expression of cyclin A and cyclin D were analyzed. Our results show that melatonin decreased PSC viability in a time- and concentration-dependent manner. This effect was not inhibited by treatment of cells with MT1, MT2, calmodulin, or ROR-alpha inhibitors prior to melatonin addition. Activation of caspase-3 in response to melatonin was detected. The expression of cyclin A and cyclin D was decreased in cells treated with melatonin. Finally, changes in BrdU incorporation into the newly synthesized DNA of proliferating cells were also observed in the presence of melatonin. We conclude that melatonin, at pharmacological concentrations, modulates proliferation of PSC through activation of apoptosis and involving crucial regulators of the cell cycle. These actions might not require specific melatonin receptors. Our observations suggest that melatonin, at high doses, could potentially exert anti-fibrotic effects and, thus, could be taken into consideration as supportive treatment in the therapy of pancreatic diseases.
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Affiliation(s)
- Matias Estaras
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, E-10003, Cáceres, Spain
| | - Fernando J Peña
- Laboratory of Equine Reproduction and Equine Spermatology, Veterinary Teaching Hospital, University of Extremadura, Cáceres, Spain
| | - José A Tapia
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, E-10003, Cáceres, Spain
| | | | - Jose M Mateos
- Department of Gastroenterology, San Pedro de Alcantara Hospital, Cáceres, Spain
| | - Daniel Vara
- Department of Gastroenterology, San Pedro de Alcantara Hospital, Cáceres, Spain
| | - Vicente Roncero
- Unit of Histology and Pathological Anatomy, Veterinary Faculty, University of Extremadura, Cáceres, Spain
| | - Gerardo Blanco
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, Badajoz, Spain
| | - Diego Lopez
- Hepatobiliary-Pancreatic Surgery and Liver Transplant Unit, Infanta Cristina Hospital, Badajoz, Spain
| | - Gines M Salido
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, E-10003, Cáceres, Spain
| | - Antonio Gonzalez
- Institute of Molecular Pathology Biomarkers, University of Extremadura, Avenida de las Ciencias s/n, E-10003, Cáceres, Spain.
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26
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Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment. Pathol Res Pract 2020; 216:152919. [PMID: 32171553 DOI: 10.1016/j.prp.2020.152919] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 02/21/2020] [Accepted: 03/07/2020] [Indexed: 12/15/2022]
Abstract
Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.
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27
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Lu KH, Lin RC, Yang JS, Yang WE, Reiter RJ, Yang SF. Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma. Cells 2019; 8:E1618. [PMID: 31842295 PMCID: PMC6952995 DOI: 10.3390/cells8121618] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/06/2019] [Accepted: 12/09/2019] [Indexed: 02/06/2023] Open
Abstract
Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11-15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.
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Affiliation(s)
- Ko-Hsiu Lu
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan; (K.-H.L.); (R.-C.L.)
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
| | - Renn-Chia Lin
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan; (K.-H.L.); (R.-C.L.)
- School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan
- Division of Hyperbaric Oxygen Therapy and Wound Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Jia-Sin Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (W.-E.Y.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Wei-En Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (W.-E.Y.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
| | - Russel J. Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan; (J.-S.Y.); (W.-E.Y.)
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan
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28
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Fathizadeh H, Mirzaei H, Asemi Z. Melatonin: an anti-tumor agent for osteosarcoma. Cancer Cell Int 2019; 19:319. [PMID: 31798348 PMCID: PMC6884844 DOI: 10.1186/s12935-019-1044-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 11/22/2019] [Indexed: 12/23/2022] Open
Abstract
Osteosarcoma is the most common bone tumors which consisted of malignant mesenchymal cells generating osteoid and immature bone. It has been showed that osteosarcoma is common in children and adolescents and shows high mortality rate. A variety of therapeutic approaches (i.e., resection surgery, combined with chemotherapy and radiotherapy) have been used as conventional treatments in patients with osteosarcoma. Despite several attempts to improve therapeutic response, the rate of survival for osteosarcoma has not changed during the past 3 decades. Therefore, the discovery and developing new effective therapeutic platforms are required. Along to the established anti-cancer agents, some physiological regulators such melatonin, have been emerged as new anti-cancer agents. Melatonin is an indolamine hormone which is secreted from the pineal glands during the night and acts as physiological regulator. Given that melatonin shows a wide spectrum anti-tumor impacts. Besides different biologic activities of melatonin (e.g., immunomodulation and antioxidant properties), melatonin has a crucial role in the formation of bones, and its deficiency could be directly related to bone cancers. Several in vitro and in vivo experiments evaluated the effects of melatonin on osteosarcoma and other types of bone cancer. Taken together, the results of these studies indicated that melatonin could be introduced as new therapeutic candidate or as adjuvant in combination with other anti-tumor agents in the treatment of osteosarcoma. Herein, we summarized the anti-tumor effects of melatonin for osteosarcoma cancer as well as its mechanism of action.
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Affiliation(s)
- Hadis Fathizadeh
- 1Department of Microbiology, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Hamed Mirzaei
- 2Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Zatollah Asemi
- 2Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
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Kleszczyński K, Kim TK, Bilska B, Sarna M, Mokrzynski K, Stegemann A, Pyza E, Reiter RJ, Steinbrink K, Böhm M, Slominski AT. Melatonin exerts oncostatic capacity and decreases melanogenesis in human MNT-1 melanoma cells. J Pineal Res 2019; 67:e12610. [PMID: 31532834 PMCID: PMC7924888 DOI: 10.1111/jpi.12610] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/23/2019] [Accepted: 09/09/2019] [Indexed: 12/22/2022]
Abstract
Melanogenesis is a key parameter of differentiation in melanocytes and melanoma cells; therefore, search for factors regulating this pathway are strongly desired. Herein, we investigated the effects of melatonin, a ubiquitous physiological mediator that is found throughout animals and plants. In mammals, the pineal gland secretes this indoleamine into the blood circulation to exert an extensive repertoire of biological activities. Our in vitro assessment indicates an oncostatic capacity of melatonin in time-dependent manner (24, 48, 72 hours) in highly pigmented MNT-1 melanoma cells. The similar pattern of regulation regarding cell viability was observed in amelanotic Sk-Mel-28 cells. Subsequently, MNT-1 cells were tested for the first time for evaluation of melanin/melatonin interaction. Thus primary, electron paramagnetic resonance (EPR) spectroscopy demonstrated that melatonin reduced melanin content. Artificially induced disturbances of melanogenesis by selected inhibitors (N-phenylthiourea or kojic acid) were slightly antagonized by melatonin. Additionally, analysis using transmission electron microscopy has shown that melatonin, particularly at higher dose of 10-3 mol/L, triggered the appearance of premelanosomes (stage I-II of melanosome) and MNT-1 cells synthesize de novo endogenous melatonin shown by LC-MS. In conclusion, these studies show a melanogenic-like function of melatonin suggesting it as an advantageous agent for treatment of pigmentary disorders.
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Affiliation(s)
| | - Tae-Kang Kim
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Bernadetta Bilska
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Michal Sarna
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Krystian Mokrzynski
- Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Agatha Stegemann
- Department of Dermatology, University of Münster, Münster, Germany
| | - Elżbieta Pyza
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, Kraków, Poland
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX, USA
| | | | - Markus Böhm
- Department of Dermatology, University of Münster, Münster, Germany
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
- Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, USA
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30
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Çetin Altındal D, Gümüşderelioğlu M. Dual-functional melatonin releasing device loaded with PLGA microparticles and cyclodextrin inclusion complex for osteosarcoma therapy. J Drug Deliv Sci Technol 2019. [DOI: 10.1016/j.jddst.2019.05.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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31
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Çetin Altındal D, James EN, Kaplan DL, Gümüşderelioğlu M. Melatonin-induced osteogenesis with methanol-annealed silk materials. J BIOACT COMPAT POL 2019. [DOI: 10.1177/0883911519847489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Melatonin, a hormone produced in the pineal gland, has been investigated for bone repair, remodeling, osteoporosis, as well as osseointegration of the implants. In this study, different concentrations of melatonin (0–2000-µM) were embedded into silk films annealed by methanol or water. Then, their capacity to differentiate human mesenchymal stem cells into osteoblasts was investigated for bone tissue regeneration. While methanol-annealed silk films have ~55% crystallinity, room-temperature water-annealed silk films have ~30% crystallinity by depending upon their different β-sheet contents. Melatonin-loaded silk films exhibited an initial burst release followed by a continuous release for up to 5 days, and the β-sheet content of silk films did not affect the release behavior of melatonin, an amphiphilic molecule. Moreover, human mesenchymal stem cells exhibited an increase in osteogenic markers such as alkaline phosphatase activity, osteocalcin, and runt-related transcription factor 2 expressions on the melatonin-loaded methanol-annealed silk films in both proliferation and osteogenic media. The bioactivity of the melatonin-modified silk films was further confirmed by the enhanced mineralization compared to silk films alone. This study demonstrated the feasibility of developing melatonin-loaded silk materials and the positive effect of releasing melatonin at micromolar concentrations on osteogenic differentiation of human mesenchymal stem cells cultured especially in osteogenic medium.
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Affiliation(s)
- Damla Çetin Altındal
- Department of Chemical Engineering, Hacettepe University, Ankara, Turkey
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - Eric N James
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
| | - David L Kaplan
- Department of Biomedical Engineering, Tufts University, Medford, MA, USA
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32
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An insight into the scientific background and future perspectives for the potential uses of melatonin. ACTA ACUST UNITED AC 2019. [DOI: 10.1016/j.ejbas.2015.05.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Lu KH, Su SC, Lin CW, Hsieh YH, Lin YC, Chien MH, Reiter RJ, Yang SF. Melatonin attenuates osteosarcoma cell invasion by suppression of C-C motif chemokine ligand 24 through inhibition of the c-Jun N-terminal kinase pathway. J Pineal Res 2018; 65:e12507. [PMID: 29766567 DOI: 10.1111/jpi.12507] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 04/09/2018] [Indexed: 12/21/2022]
Abstract
Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor-suppressing properties for a myriad of tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C-C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2, respectively, in a dose-dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN-JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin-mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis.
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Affiliation(s)
- Ko-Hsiu Lu
- Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan
| | - Chiao-Wen Lin
- Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
- Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
| | - Ya-Chiu Lin
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Ming-Hsien Chien
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Russel J Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
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Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Najafi M, Sahebkar A. Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment. J Cell Physiol 2018; 234:5613-5627. [PMID: 30238978 DOI: 10.1002/jcp.27391] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Accepted: 08/17/2018] [Indexed: 12/31/2022]
Abstract
Cancer remains among the most challenging human diseases. Several lines of evidence suggest that carcinogenesis is a complex process that is initiated by DNA damage. Exposure to clastogenic agents such as heavy metals, ionizing radiation (IR), and chemotherapy drugs may cause chronic mutations in the genomic material, leading to a phenomenon named genomic instability. Evidence suggests that genomic instability is responsible for cancer incidence after exposure to carcinogenic agents, and increases the risk of secondary cancers following treatment with radiotherapy or chemotherapy. Melatonin as the main product of the pineal gland is a promising hormone for preventing cancer and improving cancer treatment. Melatonin can directly neutralize toxic free radicals more efficiently compared with other classical antioxidants. In addition, melatonin is able to regulate the reduction/oxidation (redox) system in stress conditions. Through regulation of mitochondrial nction and inhibition of pro-oxidant enzymes, melatonin suppresses chronic oxidative stress. Moreover, melatonin potently stimulates DNA damage responses that increase the tolerance of normal tissues to toxic effect of IR and may reduce the risk of genomic instability in patients who undergo radiotherapy. Through these mechanisms, melatonin attenuates several side effects of radiotherapy and chemotherapy. Interestingly, melatonin has shown some synergistic properties with IR and chemotherapy, which is distinct from classical antioxidants that are mainly used for the alleviation of adverse events of radiotherapy and chemotherapy. In this review, we describe the anticarcinogenic effects of melatonin and also its possible application in clinical oncology.
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Affiliation(s)
- Bagher Farhood
- Departments of Medical Physics and Radiology, Faculty of Paramedical Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Neda Khanlarkhani
- Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Najafi
- Departments of Radiology and Nuclear Medicine, School of Paramedical Sciences, Kermanshah University of Medical Science, Kermanshah, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Qu H, Xue Y, Lian W, Wang C, He J, Fu Q, Zhong L, Lin N, Lai L, Ye Z, Wang Q. Melatonin inhibits osteosarcoma stem cells by suppressing SOX9-mediated signaling. Life Sci 2018; 207:253-264. [PMID: 29689273 DOI: 10.1016/j.lfs.2018.04.030] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 04/15/2018] [Accepted: 04/17/2018] [Indexed: 12/30/2022]
Abstract
AIMS Melatonin (N-acetyl-5-methoxytryptamine) has been reported to suppress epithelial-mesenchymal transition and cancer stem cells in some types of cancer. However, the effects of melatonin on the osteosarcoma stem cells, epithelial-mesenchymal transition and metastasis of osteosarcoma are still not clear. The present study was conducted to dissect the activity of melatonin on the osteosarcoma stem cells and the underlying mechanisms. MAIN METHODS MTT, wound healing, transwell assay and western blotting were conducted to determine the effect of melatonin on osteosarcoma cell invasion and migration and downregulation of SOX9-mediated signaling. Tumor spheroid assay and FACS analysis were performed to analyze the inhibition of the osteosarcoma stem cells. In vivo model for tumor formation and metastasis from single cell clone was used to evaluate the suppression of osteosarcoma stem cells by melatonin. KEY FINDINGS We demonstrated that melatonin potently suppresses the migration and invasion of osteosarcoma cells. Furthermore, melatonin significantly inhibits the sarcosphere formation of osteosarcoma stem cells and regulates EMT markers of osteosarcoma cells. In vivo mice model showed that melatonin significantly inhibits the initiation and metastasis of osteosarcoma. SOX9 is the key transcription factor mediating the effect of melatonin. Melatonin inhibited of cancer stem cell by down-regulation of SOX9-mediated signaling pathway in osteosarcoma. SIGNIFICANCE Collectively, these results deepen the understanding of the biological functions of melatonin and provide new insights for the intervention of osteosarcoma stem cells.
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Affiliation(s)
- Hao Qu
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Yue Xue
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Wenwen Lian
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Cong Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Jia He
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qihong Fu
- Hangzhou Normal University School of Clinical Medicine, Hangzhou 311121, China
| | - Lijia Zhong
- Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Nong Lin
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lihua Lai
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhaoming Ye
- Department of Orthopedic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.
| | - Qingqing Wang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
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Kocyigit A, Guler EM, Karatas E, Caglar H, Bulut H. Dose-dependent proliferative and cytotoxic effects of melatonin on human epidermoid carcinoma and normal skin fibroblast cells. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2018; 829-830:50-60. [PMID: 29704993 DOI: 10.1016/j.mrgentox.2018.04.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 12/27/2022]
Abstract
New in vitro studies have demonstrated that N-acetyl-5-methoxytryptamine (Melatonin) has cytotoxic and apoptotic effects on various cell types although most of the previous investigations document that it is a potent antioxidant. However, the precise molecular mechanism(s) of its effects are not fully elucidated. In this study, we examined dose-dependent cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of melatonin in human epidermoid carcinoma cells (A-431) and human normal skin fibroblastic cells (CCD-1079Sk). The cells were incubated with different doses of melatonin (0.031-5 mM) for 24 h. Cell viability was assessed based on luminometric ATP cell viability assay. Intracellular ROS was detected using 2,7-dichlorodihydrofluorescein-diacetate (H2DCF-DA) fluorescent probes. Genotoxicity was evaluated by alkaline single cell gel electrophoresis assay (Comet Assay). Apoptosis was evaluated by western blotting, DAPI staining, acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide double staining methods Mitochondrial membrane potentials were measured by flow cytometry. Although lower doses of melatonin (0.031-0.06 mM) increased cell proliferation and decreased ROS generation, higher doses (0.125-5 mM) markedly inhibited the cell viability, induced DNA damage, apoptosis and ROS generation. Cytotoxic, genotoxic, apoptotic and ROS generating effects were significantly higher in cancer cells than those observed in normal cells. Melatonin-induced cell death, and ROS generating activity were effectively inhibited by N-acetyl-l-cysteine (NAC) In conclusion, at low doses, melatonin has proliferative effects on both cancer and normal cells, whereas high concentrations have cytotoxic effects. Cytotoxic, genotoxic and apoptotic effects at higher doses of melatonin may be due to its ROS production capacity.
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Affiliation(s)
- Abdurrahim Kocyigit
- Bezmialem Vakif University, Medical Faculty, Department of Medical Biochemistry, 93034 Istanbul, Turkey.
| | - Eray Metin Guler
- Bezmialem Vakif University, Medical Faculty, Department of Medical Biochemistry, 93034 Istanbul, Turkey.
| | - Ersin Karatas
- Bezmialem Vakif University, Medical Faculty, Department of Medical Biochemistry, 93034 Istanbul, Turkey.
| | - Hifa Caglar
- Bezmialem Vakif University, Medical Faculty, Department of Medical Biochemistry, 93034 Istanbul, Turkey.
| | - Huri Bulut
- Bezmialem Vakif University, Medical Faculty, Department of Medical Biochemistry, 93034 Istanbul, Turkey.
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37
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Talib WH. Melatonin and Cancer Hallmarks. Molecules 2018; 23:molecules23030518. [PMID: 29495398 PMCID: PMC6017729 DOI: 10.3390/molecules23030518] [Citation(s) in RCA: 140] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 02/09/2018] [Accepted: 02/19/2018] [Indexed: 02/07/2023] Open
Abstract
Melatonin is a natural indoleamine produced by the pineal gland that has many functions, including regulation of the circadian rhythm. Many studies have reported the anticancer effect of melatonin against a myriad of cancer types. Cancer hallmarks include sustained proliferation, evading growth suppressors, metastasis, replicative immortality, angiogenesis, resisting cell death, altered cellular energetics, and immune evasion. Melatonin anticancer activity is mediated by interfering with various cancer hallmarks. This review summarizes the anticancer role of melatonin in each cancer hallmark. The studies discussed in this review should serve as a solid foundation for researchers and physicians to support basic and clinical studies on melatonin as a promising anticancer agent.
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Affiliation(s)
- Wamidh H Talib
- Department of Clinical Pharmacy and Therapeutics, Applied Science Private University, Amman 11931-166, Jordan.
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38
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Melatonin and breast cancer: Evidences from preclinical and human studies. Crit Rev Oncol Hematol 2018; 122:133-143. [DOI: 10.1016/j.critrevonc.2017.12.018] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 10/20/2017] [Accepted: 12/27/2017] [Indexed: 12/22/2022] Open
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39
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Proietti S, Cucina A, Minini M, Bizzarri M. Melatonin, mitochondria, and the cancer cell. Cell Mol Life Sci 2017; 74:4015-4025. [PMID: 28785807 PMCID: PMC11107593 DOI: 10.1007/s00018-017-2612-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 08/03/2017] [Indexed: 12/12/2022]
Abstract
The long-recognized fact that oxidative stress within mitochondria is a hallmark of mitochondrial dysfunction has stimulated the development of mitochondria-targeted antioxidant therapies. Melatonin should be included among the pharmacological agents able to modulate mitochondrial functions in cancer, given that a number of relevant melatonin-dependent effects are triggered by targeting mitochondrial functions. Indeed, melatonin may modulate the mitochondrial respiratory chain, thus antagonizing the cancer highly glycolytic bioenergetic pathway of cancer cells. Modulation of the mitochondrial respiratory chain, together with Ca2+ release and mitochondrial apoptotic effectors, may enhance the spontaneous or drug-induced apoptotic processes. Given that melatonin may efficiently counteract the Warburg effect while stimulating mitochondrial differentiation and mitochondrial-based apoptosis, it is argued that the pineal neurohormone could represent a promising new perspective in cancer treatment strategy.
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Affiliation(s)
- Sara Proietti
- Department of Surgery, "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161, Rome, Italy
| | - Alessandra Cucina
- Department of Surgery, "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161, Rome, Italy
| | - Mirko Minini
- Department of Surgery, "Pietro Valdoni", Sapienza University of Rome, Via Antonio Scarpa 14, 00161, Rome, Italy
| | - Mariano Bizzarri
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy.
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40
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Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K. Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci 2017; 18:E843. [PMID: 28420185 PMCID: PMC5412427 DOI: 10.3390/ijms18040843] [Citation(s) in RCA: 318] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/05/2017] [Accepted: 04/06/2017] [Indexed: 12/21/2022] Open
Abstract
There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin's co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Sergio A Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Del Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico.
| | - Dun-Xian Tan
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | | | - Lilan Qin
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan, Medical University, Taichung 40201, Taiwan.
| | - Kexin Xu
- Department of Molecular Medicine, UT Health, San Antonio, TX 78229, USA.
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41
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Letra-Vilela R, Sánchez-Sánchez AM, Rocha AM, Martin V, Branco-Santos J, Puente-Moncada N, Santa-Marta M, Outeiro TF, Antolín I, Rodriguez C, Herrera F. Distinct roles of N-acetyl and 5-methoxy groups in the antiproliferative and neuroprotective effects of melatonin. Mol Cell Endocrinol 2016; 434:238-49. [PMID: 27402602 DOI: 10.1016/j.mce.2016.07.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 07/04/2016] [Accepted: 07/07/2016] [Indexed: 12/15/2022]
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a highly pleiotropic hormone with antioxidant, antiproliferative, oncolytic and neuroprotective properties. Here, we present evidence that the N-acetyl side chain plays a key role in melatonin's antiproliferative effect in HT22 and sw-1353 cells, but it does so at the expense of antioxidant and neuroprotective properties. Removal of the N-acetyl group enhances the antioxidant and neuroprotective properties of the indole, but it can lead to toxic methamphetamine-like effects in several cell lines. Inhibition of NFkB mimicked melatonin's antiproliferative and antioxidant effects, but not neuroprotection. Our results strongly suggest that neuroprotective and antiproliferative effects of melatonin rely on different parts of the molecule and are likely mediated by different mechanisms. We also predict that melatonin metabolism by target cells could determine whether melatonin inhibits cell proliferation, prevents toxicity or induces cell death (e.g. apoptosis or autophagy). These observations could have important implications for the rational use of melatonin in personalized medicine.
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Affiliation(s)
- Ricardo Letra-Vilela
- Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Ana María Sánchez-Sánchez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Ana Maia Rocha
- Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Vanesa Martin
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Joana Branco-Santos
- Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Noelia Puente-Moncada
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Mariana Santa-Marta
- Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal
| | - Tiago Fleming Outeiro
- Department of Neurodegeneration and Restorative Research, University Medical Center Gottingen, Waldweg 33, 37073 Gottingen, Germany; Max Planck Institute for Experimental Medicine, 37075 Goettingen, Germany
| | - Isaac Antolín
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
| | - Carmen Rodriguez
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
| | - Federico Herrera
- Cell Structure and Dynamics Laboratory, Instituto de Tecnologia Quimica e Biologica (ITQB-NOVA), Universidade Nova de Lisboa, Oeiras, Portugal.
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42
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Loureiro R, Magalhães-Novais S, Mesquita KA, Baldeiras I, Sousa IS, Tavares LC, Barbosa IA, Oliveira PJ, Vega-Naredo I. Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells. Oncotarget 2016; 6:17081-96. [PMID: 26025920 PMCID: PMC4627293 DOI: 10.18632/oncotarget.4012] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 05/08/2015] [Indexed: 12/28/2022] Open
Abstract
Although melatonin oncostatic and cytotoxic effects have been described in different types of cancer cells, the specific mechanisms leading to its antitumoral effects and their metabolic context specificity are still not completely understood. Here, we evaluated the effects of melatonin in P19 embryonal carcinoma stem cells (CSCs) and in their differentiated counterparts, cultured in either high glucose medium or in a galactose (glucose-free) medium which leads to glycolytic suppression and increased mitochondrial metabolism. We found that highly glycolytic P19 CSCs were less susceptible to melatonin antitumoral effects while cell populations relying on oxidative metabolism for ATP production were more affected. The observed antiproliferative action of melatonin was associated with an arrest at S-phase, decreased oxygen consumption, down-regulation of BCL-2 expression and an increase in oxidative stress culminating with caspase-3-independent cell death. Interestingly, the combined treatment of melatonin and dichloroacetate had a synergistic effect in cells grown in the galactose medium and resulted in an inhibitory effect in the highly resistant P19 CSCs. Melatonin appears to exert its antiproliferative activity in P19 carcinoma cells through a mitochondrially-mediated action which in turn allows the amplification of the effects of dichloroacetate, even in cells with a more glycolytic phenotype.
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Affiliation(s)
- Rute Loureiro
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Silvia Magalhães-Novais
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Katia A Mesquita
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Ines Baldeiras
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,School of Medicine, University of Coimbra, Coimbra, Portugal
| | - Isabel S Sousa
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Ludgero C Tavares
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Life Sciences, University of Coimbra, Coimbra, Portugal
| | - Ines A Barbosa
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Ignacio Vega-Naredo
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.,Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain
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43
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Pacini N, Borziani F. Oncostatic-Cytoprotective Effect of Melatonin and Other Bioactive Molecules: A Common Target in Mitochondrial Respiration. Int J Mol Sci 2016; 17:341. [PMID: 26959015 PMCID: PMC4813203 DOI: 10.3390/ijms17030341] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2015] [Revised: 11/27/2015] [Accepted: 12/03/2015] [Indexed: 12/27/2022] Open
Abstract
For several years, oncostatic and antiproliferative properties, as well as thoses of cell death induction through 5-methoxy-N-acetiltryptamine or melatonin treatment, have been known. Paradoxically, its remarkable scavenger, cytoprotective and anti-apoptotic characteristics in neurodegeneration models, such as Alzheimer’s disease and Parkinson’s disease are known too. Analogous results have been confirmed by a large literature to be associated to the use of many other bioactive molecules such as resveratrol, tocopherol derivatives or vitamin E and others. It is interesting to note that the two opposite situations, namely the neoplastic pathology and the neurodegeneration, are characterized by deep alterations of the metabolome, of mitochondrial function and of oxygen consumption, so that the oncostatic and cytoprotective action can find a potential rationalization because of the different metabolic and mitochondrial situations, and in the effect that these molecules exercise on the mitochondrial function. In this review we discuss historical and general aspects of melatonin, relations between cancers and the metabolome and between neurodegeneration and the metabolome, and the possible effects of melatonin and of other bioactive molecules on metabolic and mitochondrial dynamics. Finally, we suggest a common general mechanism as responsible for the oncostatic/cytoprotective effect of melatonin and of other molecules examined.
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Affiliation(s)
- Nicola Pacini
- Laboratorio Privato di Biochimica F. Pacini, via trabocchetto 10, 89126 Reggio Calabria, Italy.
| | - Fabio Borziani
- Laboratorio Privato di Biochimica F. Pacini, via trabocchetto 10, 89126 Reggio Calabria, Italy.
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44
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Murali R, Thanikaivelan P, Cheirmadurai K. Melatonin in functionalized biomimetic constructs promotes rapid tissue regeneration in Wistar albino rats. J Mater Chem B 2016; 4:5850-5862. [DOI: 10.1039/c6tb01221c] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Biomimetic collagen–poly(dialdehyde) gum acacia based hybrid scaffolds with a synergistic combination of melatonin were prepared to regenerate tissue formation in wound-healing applications.
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Affiliation(s)
- Ragothaman Murali
- Advanced Materials Laboratory
- Central Leather Research Institute (Council of Scientific and Industrial Research)
- Chennai 600020
- India
| | - Palanisamy Thanikaivelan
- Advanced Materials Laboratory
- Central Leather Research Institute (Council of Scientific and Industrial Research)
- Chennai 600020
- India
| | - Kalirajan Cheirmadurai
- Advanced Materials Laboratory
- Central Leather Research Institute (Council of Scientific and Industrial Research)
- Chennai 600020
- India
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45
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Melatonin/HPβCD complex: Microwave synthesis, integration with chitosan scaffolds and inhibitory effects on MG-63CELLS. Int J Pharm 2015; 496:801-11. [DOI: 10.1016/j.ijpharm.2015.11.028] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 11/13/2015] [Accepted: 11/14/2015] [Indexed: 11/23/2022]
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46
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Altındal DÇ, Gümüşderelioğlu M. Melatonin releasing PLGA micro/nanoparticles and their effect on osteosarcoma cells. J Microencapsul 2015; 33:53-63. [PMID: 26605784 DOI: 10.3109/02652048.2015.1115901] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Melatonin loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles and microparticles in the diameter of ∼200 nm and 3.5 μm, respectively, were prepared by emulsion-diffusion-evaporation method. Melatonin entrapment into the particles was significantly improved with the addition of 0.2% (w/v) melatonin into the aqueous phase and encapsulation efficiencies were found as 14 and 27% for nanoparticles and microparticles, respectively. At the end of 40 days, ∼70% of melatonin was released from both of particles, with high burst release. Both blank and melatonin loaded PLGA nanoparticles caused toxic effect on the MG-63 cells due to their uptake by the cells. However, when 0.05 mg microparticle that is carrying ∼1.7 μg melatonin was added to the cm(2) of culture, inhibitory effect of melatonin on the cells were obviously observed. The results would provide an expectation about the usage of melatonin as an adjunct to the routine chemotherapy of osteosarcoma by encapsulating it into a polymeric carrier system.
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Affiliation(s)
- Damla Çetin Altındal
- a Chemical Engineering Department , Hacettepe University , Beytepe , Ankara , Turkey
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47
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Zhou W, Zhu Y, Chen S, Xu R, Wang K. Fibroblast growth factor receptor 1 promotes MG63 cell proliferation and is associated with increased expression of cyclin-dependent kinase 1 in osteosarcoma. Mol Med Rep 2015; 13:713-9. [PMID: 26648125 PMCID: PMC4686061 DOI: 10.3892/mmr.2015.4597] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 08/05/2015] [Indexed: 12/12/2022] Open
Abstract
Osteosarcoma is the most common type of malignant bone tumor in adolescents and young adults. However, current understanding of osteosarcomagenesis remains limited. In the present study, the role of fibroblast growth factor receptor 1 (FGFR1) in human osteosarcoma cell proliferation was investigated, and the possible pathways that contribute to FGFR1‑mediated osteosarcoma cell proliferation were examined using microarray analysis. The expression of FGFR1 in osteosarcoma tissues was assessed by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. The results demonstrated that FGFR1 was markedly increased in osteosarcoma tissues, and that the overexpression of FGFR1 in MG63 cells significantly promoted cell proliferation, as observed using the cell viability assay. In addition, FGFR1‑mediated cell proliferation was closely associated with cell cycle re‑distribution, as determined by microarray analysis. Western blotting identified that the expression of cyclin-dependent kinase 1 (CDK1) was correspondingly increased in response to the overexpression of FGFR1. These results indicated that FGFR1 contributes to cell proliferation in osteosarcoma MG63 cells, and FGFR1 mediated cell proliferation may be attributed to the regulation of the cell cycle regulator, CDK1. These findings provide evidence to support the potential use of molecule target therapy against FGFR1 as a promising strategy in osteosarcoma treatment and prevention.
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Affiliation(s)
- Wei Zhou
- Department of Orthopaedics, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Yue Zhu
- Department of Orthopaedics, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Song Chen
- Department of Orthopaedics, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Ruijun Xu
- Department of Orthopaedics, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Kunzheng Wang
- Department of Orthopaedics, The Second Hospital Affiliated to Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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48
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Molecular aspects of melatonin (MLT)-mediated therapeutic effects. Life Sci 2015; 135:147-57. [DOI: 10.1016/j.lfs.2015.06.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 06/15/2015] [Accepted: 06/23/2015] [Indexed: 01/08/2023]
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49
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Codenotti S, Battistelli M, Burattini S, Salucci S, Falcieri E, Rezzani R, Faggi F, Colombi M, Monti E, Fanzani A. Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines. Oncol Rep 2015; 34:279-87. [PMID: 25998836 DOI: 10.3892/or.2015.3987] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 03/30/2015] [Indexed: 11/06/2022] Open
Abstract
Melatonin is a small indole produced by the pineal gland and other tissues, and has numerous functions that aid in the maintenance of the whole body homeostasis, ranging from the regulation of circadian rhythms and sleep to protection from oxidative stress. Melatonin has also been reported to counteract cell growth and chemoresistance in different types of cancer. In the present study, we investigated the effects of exogenous melatonin administration on different human cell lines and primary mouse tumor cultures of rhabdomyosarcoma (RMS), the most frequent soft tissue sarcoma affecting childhood. The results showed that melatonin significantly affected the behavior of RMS cells, leading to inhibition of cell proliferation and impairment of myogenic differentiation followed by increased apoptotic cell death, as observed by immunoblotting analysis of apoptosis-related markers including Bax, Bcl-2 and caspase-3. Similar findings were observed using a combination of microscopy techniques, including scanning/transmission electron and confocal microscopy. Furthermore, melatonin in combination with doxorubicin or cisplatin, two compounds commonly used for the treatment of solid tumors, increased the sensitivity of RMS cells to apoptosis. These data indicated that melatonin may be effective in counteracting RMS tumor growth and chemoresistance.
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Affiliation(s)
- Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
| | - Michela Battistelli
- Department of Earth, Life and Environmental Sciences (DiSTeVA), University Carlo Bo, I-61029 Urbino, Italy
| | - Sabrina Burattini
- Department of Earth, Life and Environmental Sciences (DiSTeVA), University Carlo Bo, I-61029 Urbino, Italy
| | - Sara Salucci
- Department of Earth, Life and Environmental Sciences (DiSTeVA), University Carlo Bo, I-61029 Urbino, Italy
| | - Elisabetta Falcieri
- Department of Earth, Life and Environmental Sciences (DiSTeVA), University Carlo Bo, I-61029 Urbino, Italy
| | - Rita Rezzani
- Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
| | - Fiorella Faggi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
| | - Marina Colombi
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
| | - Eugenio Monti
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
| | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, I-25123 Brescia, Italy
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Effect of Melatonin on the Extracellular-Regulated Kinase Signal Pathway Activation and Human Osteoblastic Cell Line hFOB 1.19 Proliferation. Int J Mol Sci 2015; 16:10337-53. [PMID: 25961946 PMCID: PMC4463649 DOI: 10.3390/ijms160510337] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 04/21/2015] [Accepted: 04/27/2015] [Indexed: 02/06/2023] Open
Abstract
It has been shown that melatonin may affect bone metabolism. However, it is controversial whether melatonin could promote osteoblast proliferation, and the precise molecular mechanism of melatonin on osteoblast proliferation is still obscure. In this study, the results of the CCK-8 assay showed that melatonin significantly promoted human osteoblastic cell line hFOB 1.19 cell proliferation at 1, 2.5, 5, 10, 25, 50 and 100 µM concentrations for 24 h, but there were no significant differences among the groups. Western blot demonstrated that 10 µM melatonin significantly promoted ERK1/2 phosphorylation. Furthermore, we also detected the phosphorylation of c-Raf, MEK1/2, p90RSK and MSK1, and all of them increased with 10 µM melatonin. U0126 (a selective inhibitor of MEK that disrupts downstream activation of ERK1/2) downregulated the phosphorylation of ERK1/2, p90RSK and MSK1. U0126 also attenuated the proliferation of osteoblasts stimulated by melatonin. In conclusion, this study for the first time indicates that melatonin (10 nM–100 µM) promotes the proliferation of a human osteoblastic cell line hFOB 1.19 through activation of c-Raf, MEK1/2, ERK1/2, p90RSK and MSK1.
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